1. Histone deacetylase inhibitor apicidin-mediated drug resistance: Involvement of P-glycoprotein
- Author
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Kim, Yong Kee, Kim, Nam Hyun, Hwang, Jee Won, Song, Yong-Jin, Park, Yeon-Suk, Seo, Dong-Wan, Lee, Hoi Young, Choi, Wahn Soo, Han, Jeung-Whan, and Kim, Su-Nam
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P-glycoprotein , *GLYCOPROTEINS , *APOPTOSIS , *MULTIDRUG resistance - Abstract
Abstract: Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), resulting in an increased drug efflux. In this study, we show that the histone deacetylase (HDAC) inhibitor apicidin leads to resistance of HeLa cells to paclitaxel through the induction of P-gp expression. Furthermore, apicidin dramatically increases the release of a fluorescent P-gp substrate, rhodamine 123, from cells. In parallel, apicidin resistance to the apoptotic potential of paclitaxel is associated with induction of P-gp expression in HeLa cells, as evidenced by specific inhibition of P-gp function using either the pharmacological inhibitor verapamil or RNA silencing. We also demonstrate the contribution of apicidin-induced functional P-gp expression to drug resistance using KB cells. Failure of P-gp induction by apicidin does not reverse paclitaxel-induced cytotoxicity in the cells. Although HDAC inhibitors are widely appreciated as a new class of anti-tumor agent, our findings clearly demonstrate that apicidin treatment may lead to P-gp-mediated resistance to other anti-tumor agents, suggesting a need for careful design of clinical applications using HDAC inhibitors. [Copyright &y& Elsevier]
- Published
- 2008
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